Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain tumor, accounting for 52% of all primary brain tumor cases and 20% of all intracranial tumors. The median survival time for a newly diagnosed patient is approximately one year (Krex et al., Brain, 130:2596-606, 2007). Current methods of treatment involve chemotherapy, radiotherapy, and/or surgery, all of which are palliative measures that are not curative (Nicholas, Expert Rev Anticancer Ther, 7:S23-7, 2007; Benitez et al., Curr Med Chem, 15:729-42, 2008; Chang et al., Clin Adv Hematol Oncol, 5:894-902, 2007; and Reardon et al., Curr Treat Options Oncol, 9:1-22, 2008). One problem with current treatment methods is that even with complete gross surgical resection of the tumor combined with the best available treatment, recurrence of the tumor is nearly impossible to prevent, and consequently the long-term survival rate for GBM patients is extremely low.
It has been hypothesized that tumors are heterogeneous and only some of the tumor cells with stem-like properties are able to initiate and sustain tumor development (Reya et al., Nature, 414:105-11, 2001; Pardal et al., Nat Rev Cancer, 3:895-902, 2003; and Dalerba et al, Annu Rev Med, 58:267-84, 2007). It has been further postulated that current therapies targeting the bulk tumor are unable to completely eliminate these tumor-initiating subpopulations, leading to tumor recurrence and treatment failure (Eyler and Rich, J Clin Oncol, 26:2839-45, 2008; and Jiang et al., Leukemia, 21:926-35, 2007). Therapies optimized for eliminating these subpopulations would therefore be more effective in preventing recurrence than those targeting the bulk tumor (Eyler and Rich, J Clin Oncol, 26:2839-45, 2008; and Sims et al., Nat Clin Pract Oncol, 4:516-25, 2007). While conceptually appealing, therapies that target these tumor-initiating cells have yet to be developed for use in clinical practice.
Tumor-initiating cells were initially identified in hematological malignancies and later in many types of solid tumors, including brain tumors. A subpopulation of cells that are positive for the glycosylation-dependent conformational CD133 epitopes (AC133 and/or AC141) have been identified in malignant gliomas, and this subpopulation has been shown to have significantly enhanced potency for initiating tumors in immunocompromised mice (Singh et al., Cancer Res, 63:5821-8, 2003; Singh et al., Oncogene, 23:7267-73, 2004; Singh et al., Nature, 432:396-401, 2004; Yuan et al., Oncogene, 23:9392-400, 2004; and Bidlingmaier et al., J Mol Med, 86:1025-32, 2008). In one study, as few as 100 CD133 epitope-positive human glioma cells were shown to be capable of tumor initiation in immunocompromised mice, whereas 100,000 CD133 epitope-negative cells isolated from the same tumor mass were non-tumorigenic (Singh et al., Nature, 432:396-401, 2004).
Thus, a significant biomedical need exists for compositions that target GBM tumor-initiating cells.